H. Jack West, MD: Let’s turn to stage IV disease. This affects lots of our patients, and it’s been an interesting, practice-changing year, I would say, in advanced non-small cell lung cancer, particularly with the patients without a driver mutation. We are still testing for this up front and siphoning those patients toward targeted therapies appropriately. But for the patients without a driver mutation, what would you say is your approach for patients with PD-L1 levels of 1% to 49%? Hoss, I’ll start with you.

Hossein Borghaei, DO: I think that’s a simple question for me. For me, the practice is now a combination of chemotherapy plus I-O [immuno-oncology]. I think the results of several studies now—whether you have squamous cell histology, whether you have nonsquamous histology, a different chemotherapy backbone—they all seem to suggest that I-O plus chemotherapy is superior in terms of response rate, progression-free survival [PFS], and overall survival in a number of these studies. So my practice has completely shifted to the use of I-O plus chemotherapy in a less than 50% PD-L1–positive patient population.

H. Jack West, MD: OK. Charu?

Charu Aggarwal, MD, MPH: So let me ask you this: I agree, but if there’s a patient who came with a performance status of 2, 1% to 49%, and you didn’t really think that that patient could get a triplet, would you do pembrolizumab based on KEYNOTE-042?

Hossein Borghaei, DO: I’m open to the idea. I really don’t have anything against that. I would also argue that we have 4 randomized phase III studies suggesting that I-O post chemotherapy can be quite effective in that patient population. And we have long-term follow-up and survival data for those 4 randomized phase III studies. So the sequential approach if somebody cannot get the triplet therapy up front is still a viable option. But I agree that KEYNOTE-042 gives you an option, because there was no detrimental effect compared with chemotherapy if you use single-agent pembrolizumab.

H. Jack West, MD: Let’s talk about the implications. I think we all agree that chemotherapy/I-O is a very appealing and appropriate choice for most of these patients. It didn’t add any prohibitive toxicity, just basically what you’d expect, superimposing our experience of chemotherapy doublets and single-agent immunotherapy, so no real surprises. And it’s really just histology-appropriate chemotherapy. Is it going to be cis [cisplatin] or carbo [carboplatin]? Usually with us it’s carbo, and pemetrexed for the nonsquamous and a carbo with a taxane, either paclitaxel or nab-paclitaxel in squamous.

So that was KEYNOTE-189, really setting the standard for most of these patients with nonsquamous, and KEYNOTE-407 for the squamous. You brought up KEYNOTE-042, which was pembrolizumab versus a histology appropriate doublet for 1% or greater. It was a positive trial, but it looks like it was really propelled by the high–PD-L1 patients.

Hossein Borghaei, DO: Oh sure, absolutely.

H. Jack West, MD: And the low PD-L1s diluted the results, just not enough to make it negative. And the results showed that, yes, they were comparable, just not better with pembrolizumab.

Hossein Borghaei, DO: Correct.

H. Jack West, MD: But that trial did not allow crossover, and just 20% of the patients ever crossed over to what you mentioned, appropriately, as our clear standard of care before this. We have very strong evidence that there is a highly significant survival benefit to sequential therapy. To me, this suggests that the 80% who didn’t get that got substandard care, at least by our contemporary definition. And that leads me to think it’s not that equivalent. Pembro [pembrolizumab] did as well as up-front chemotherapy with its hands tied behind its back. It wasn’t a fair fight, and sequential is still totally appropriate. It’s not that I think it exonerates us to do it in some circumstances for the patient who abjectly refuses or for whatever reason isn’t a candidate. But, before this, we have evidence that PS [performance status] 2 patients can and do benefit from chemotherapy doublets, even with carbo.

Hossein Borghaei, DO: Oh, sure.

H. Jack West, MD: I would just say, how do you frame the KEYNOTE-042 results? Is my interpretation fair?

Hossein Borghaei, DO: I think it is fair.

Charu Aggarwal, MD, MPH: I completely agree. I would not actually offer pembro just based on KEYNOTE-042. I think there are compelling data, both in terms of overall survival and progression-free survival, to be able to offer triplets. I would really carefully think about the reasons why I’m not able to offer a triplet. Is it toxicity? Is it age? Is it convenience? I would really examine what the limitations are before offering I-O up front for that particular 1% to 49% population.

Hossein Borghaei, DO: Yeah. I think it’s not a fair fight, and that has become something a little bit bothersome. We see this a lot in these randomized phase III trials, where a good portion of patients post progression on an inferior arm don’t really get the active drug. And if survival is confounded by all of these factors, which we know they are, then you’re right, it is a little bit of an unfair comparison. But the data are what the data are. The curves don’t show inferiority. They don’t show harm. So I think, again, it is an option. It’s not something that I do in my practice, but…

H. Jack West, MD: Yeah, I think that it does raise a bit of a question for all of the dramatically positive results of the combination arms: How much is it really a test of concurrent versus sequential versus 100% access versus 50% access when you cross over?

Hossein Borghaei, DO: Exactly.

H. Jack West, MD: These are fair issues. I think the counterpoint would be, well, at least the only way to be completely confident you’re going to give everyone access is to start with that, whether that’s real or not. It raises the question of whether there are any patients for whom chemotherapy up front without immunotherapy—even if you can do it, you might withhold it. And I would say that maybe for PS2 that would come up, maybe. We don’t have the evidence to speak to that. But are there patients where you can see a reason to do it sequentially, even if you have the ability to do it concurrently?

Hossein Borghaei, DO: Well, again, it has to do with how you interpret the data. And I’m going to raise this very controversial study, CheckMate 227, which I know is a favorite of a lot of people to beat up, but I presented the data at ASCO [American Society of Clinical Oncology] with a PD-L1–negative subpopulation, and the punch line is that the TMB [tumor mutation burden]–low—defined as less than 10 mutations per megabase—PD-L1–negative patients, whether you added I-O to chemotherapy or you gave them I-O/I-O, PFS was no better than standard chemotherapy alone. Yes, it’s a small subset. Yes, the study is not completed. Yes, we’re looking at a fraction of the patients that entered the study. All of those caveats are there, but to me, that does seem like we might be able to define, biologically, a group of patients that, based on 2 different biomarkers, TMB and PD-L1, don’t really benefit from additional I-O up front. So it is possible to say that in that patient population, starting with chemotherapy and perhaps trying I-O as a single agent after progression might be a reasonable approach until we figure out how to treat that patient population a little bit better.

So do I use it in practice right now? I’ve got to tell you, I get a little bit hesitant when I see a low TMB and negative PD-L1 in the clinic, as far as going full force with the chemo/I-O and all of that. And, again, it is one of those scenarios where I have a very in-depth discussion with the patient and try to give everybody the benefit of the doubt and sort of say, “Look, there are some studies that PD-L1-negatives may be given chemo/I-O if PFS is not better, but response and survival is definitely better.” So then it becomes one of these discussions with the patient to decide how to proceed with it.

H. Jack West, MD: So I think we’ll need to delve more into TMB a little more. I think that really needs to be fleshed out a little more. But I’ll say that I’ve had an occasional patient who is older and with a pattern of disease that’s been quite indolent where I haven’t necessarily been enthused to do this, just because if they run into toxicity issues or even if they respond, you’re not sure what they’re responding to or having this nonspecific fatigue toxicity from. And I’m not that convinced that there’s some additive or synergistic effect here as much as just getting it to them. And so for a patient who may be on the bubble for tolerability and who has a pretty indolent cancer process where I have great confidence that they will get their chance with this and get their chance with the other, I have sometimes selected that patient, as it would be perfectly fine to just ensure that they get their opportunity with the chemotherapy and their opportunity with immunotherapy. So that’s been about the only case. Most times I think that concurrent is a compelling way to go. Charu, your thoughts?

Charu Aggarwal, MD, MPH: So, I’ve not had a patient where I otherwise thought that they could get immunotherapy where I’ve reserved immunotherapy for later. I’ve certainly had patients where I didn’t think that immunotherapy was feasible because of other comorbidities or coexisting illnesses or autoimmune conditions, where right off the bat there is no way I can ever give this patient immunotherapy. I just had a patient in my clinic yesterday who is a heart transplant survivor. Immunotherapy is off the table, right? I mean, I just can never give it to them. So it never even comes into the discussion, and I proceed with chemotherapy, but I’ve not had a patient where I’ve sort of, if I’m able to give it…, reserved it for later. I’ve not had that yet.

Transcript edited for clarity.

SELECTEDLANGUAGE

Transcript:

H. Jack West, MD: Let’s turn to stage IV disease. This affects lots of our patients, and it’s been an interesting, practice-changing year, I would say, in advanced non-small cell lung cancer, particularly with the patients without a driver mutation. We are still testing for this up front and siphoning those patients toward targeted therapies appropriately. But for the patients without a driver mutation, what would you say is your approach for patients with PD-L1 levels of 1% to 49%? Hoss, I’ll start with you.

Hossein Borghaei, DO: I think that’s a simple question for me. For me, the practice is now a combination of chemotherapy plus I-O [immuno-oncology]. I think the results of several studies now—whether you have squamous cell histology, whether you have nonsquamous histology, a different chemotherapy backbone—they all seem to suggest that I-O plus chemotherapy is superior in terms of response rate, progression-free survival [PFS], and overall survival in a number of these studies. So my practice has completely shifted to the use of I-O plus chemotherapy in a less than 50% PD-L1–positive patient population.

H. Jack West, MD: OK. Charu?

Charu Aggarwal, MD, MPH: So let me ask you this: I agree, but if there’s a patient who came with a performance status of 2, 1% to 49%, and you didn’t really think that that patient could get a triplet, would you do pembrolizumab based on KEYNOTE-042?

Hossein Borghaei, DO: I’m open to the idea. I really don’t have anything against that. I would also argue that we have 4 randomized phase III studies suggesting that I-O post chemotherapy can be quite effective in that patient population. And we have long-term follow-up and survival data for those 4 randomized phase III studies. So the sequential approach if somebody cannot get the triplet therapy up front is still a viable option. But I agree that KEYNOTE-042 gives you an option, because there was no detrimental effect compared with chemotherapy if you use single-agent pembrolizumab.

H. Jack West, MD: Let’s talk about the implications. I think we all agree that chemotherapy/I-O is a very appealing and appropriate choice for most of these patients. It didn’t add any prohibitive toxicity, just basically what you’d expect, superimposing our experience of chemotherapy doublets and single-agent immunotherapy, so no real surprises. And it’s really just histology-appropriate chemotherapy. Is it going to be cis [cisplatin] or carbo [carboplatin]? Usually with us it’s carbo, and pemetrexed for the nonsquamous and a carbo with a taxane, either paclitaxel or nab-paclitaxel in squamous.

So that was KEYNOTE-189, really setting the standard for most of these patients with nonsquamous, and KEYNOTE-407 for the squamous. You brought up KEYNOTE-042, which was pembrolizumab versus a histology appropriate doublet for 1% or greater. It was a positive trial, but it looks like it was really propelled by the high–PD-L1 patients.

Hossein Borghaei, DO: Oh sure, absolutely.

H. Jack West, MD: And the low PD-L1s diluted the results, just not enough to make it negative. And the results showed that, yes, they were comparable, just not better with pembrolizumab.

Hossein Borghaei, DO: Correct.

H. Jack West, MD: But that trial did not allow crossover, and just 20% of the patients ever crossed over to what you mentioned, appropriately, as our clear standard of care before this. We have very strong evidence that there is a highly significant survival benefit to sequential therapy. To me, this suggests that the 80% who didn’t get that got substandard care, at least by our contemporary definition. And that leads me to think it’s not that equivalent. Pembro [pembrolizumab] did as well as up-front chemotherapy with its hands tied behind its back. It wasn’t a fair fight, and sequential is still totally appropriate. It’s not that I think it exonerates us to do it in some circumstances for the patient who abjectly refuses or for whatever reason isn’t a candidate. But, before this, we have evidence that PS [performance status] 2 patients can and do benefit from chemotherapy doublets, even with carbo.

Hossein Borghaei, DO: Oh, sure.

H. Jack West, MD: I would just say, how do you frame the KEYNOTE-042 results? Is my interpretation fair?

Hossein Borghaei, DO: I think it is fair.

Charu Aggarwal, MD, MPH: I completely agree. I would not actually offer pembro just based on KEYNOTE-042. I think there are compelling data, both in terms of overall survival and progression-free survival, to be able to offer triplets. I would really carefully think about the reasons why I’m not able to offer a triplet. Is it toxicity? Is it age? Is it convenience? I would really examine what the limitations are before offering I-O up front for that particular 1% to 49% population.

Hossein Borghaei, DO: Yeah. I think it’s not a fair fight, and that has become something a little bit bothersome. We see this a lot in these randomized phase III trials, where a good portion of patients post progression on an inferior arm don’t really get the active drug. And if survival is confounded by all of these factors, which we know they are, then you’re right, it is a little bit of an unfair comparison. But the data are what the data are. The curves don’t show inferiority. They don’t show harm. So I think, again, it is an option. It’s not something that I do in my practice, but…

H. Jack West, MD: Yeah, I think that it does raise a bit of a question for all of the dramatically positive results of the combination arms: How much is it really a test of concurrent versus sequential versus 100% access versus 50% access when you cross over?

Hossein Borghaei, DO: Exactly.

H. Jack West, MD: These are fair issues. I think the counterpoint would be, well, at least the only way to be completely confident you’re going to give everyone access is to start with that, whether that’s real or not. It raises the question of whether there are any patients for whom chemotherapy up front without immunotherapy—even if you can do it, you might withhold it. And I would say that maybe for PS2 that would come up, maybe. We don’t have the evidence to speak to that. But are there patients where you can see a reason to do it sequentially, even if you have the ability to do it concurrently?

Hossein Borghaei, DO: Well, again, it has to do with how you interpret the data. And I’m going to raise this very controversial study, CheckMate 227, which I know is a favorite of a lot of people to beat up, but I presented the data at ASCO [American Society of Clinical Oncology] with a PD-L1–negative subpopulation, and the punch line is that the TMB [tumor mutation burden]–low—defined as less than 10 mutations per megabase—PD-L1–negative patients, whether you added I-O to chemotherapy or you gave them I-O/I-O, PFS was no better than standard chemotherapy alone. Yes, it’s a small subset. Yes, the study is not completed. Yes, we’re looking at a fraction of the patients that entered the study. All of those caveats are there, but to me, that does seem like we might be able to define, biologically, a group of patients that, based on 2 different biomarkers, TMB and PD-L1, don’t really benefit from additional I-O up front. So it is possible to say that in that patient population, starting with chemotherapy and perhaps trying I-O as a single agent after progression might be a reasonable approach until we figure out how to treat that patient population a little bit better.

So do I use it in practice right now? I’ve got to tell you, I get a little bit hesitant when I see a low TMB and negative PD-L1 in the clinic, as far as going full force with the chemo/I-O and all of that. And, again, it is one of those scenarios where I have a very in-depth discussion with the patient and try to give everybody the benefit of the doubt and sort of say, “Look, there are some studies that PD-L1-negatives may be given chemo/I-O if PFS is not better, but response and survival is definitely better.” So then it becomes one of these discussions with the patient to decide how to proceed with it.

H. Jack West, MD: So I think we’ll need to delve more into TMB a little more. I think that really needs to be fleshed out a little more. But I’ll say that I’ve had an occasional patient who is older and with a pattern of disease that’s been quite indolent where I haven’t necessarily been enthused to do this, just because if they run into toxicity issues or even if they respond, you’re not sure what they’re responding to or having this nonspecific fatigue toxicity from. And I’m not that convinced that there’s some additive or synergistic effect here as much as just getting it to them. And so for a patient who may be on the bubble for tolerability and who has a pretty indolent cancer process where I have great confidence that they will get their chance with this and get their chance with the other, I have sometimes selected that patient, as it would be perfectly fine to just ensure that they get their opportunity with the chemotherapy and their opportunity with immunotherapy. So that’s been about the only case. Most times I think that concurrent is a compelling way to go. Charu, your thoughts?

Charu Aggarwal, MD, MPH: So, I’ve not had a patient where I otherwise thought that they could get immunotherapy where I’ve reserved immunotherapy for later. I’ve certainly had patients where I didn’t think that immunotherapy was feasible because of other comorbidities or coexisting illnesses or autoimmune conditions, where right off the bat there is no way I can ever give this patient immunotherapy. I just had a patient in my clinic yesterday who is a heart transplant survivor. Immunotherapy is off the table, right? I mean, I just can never give it to them. So it never even comes into the discussion, and I proceed with chemotherapy, but I’ve not had a patient where I’ve sort of, if I’m able to give it…, reserved it for later. I’ve not had that yet.